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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

Background:

The pharmacologic profile of the new proton pump inhibitor esomeprazole has demonstrated advantages over omeprazole that suggest clinical benefits for patients with acid-related disease.

Methods:

1960 patients with endoscopy-confirmed reflux oesophagitis (RO) were randomized to once daily esomeprazole 40 mg (n=654) or 20 mg (n=656), or omeprazole 20 mg (n=650), the standard recommended dose for RO, for up to 8 weeks in a US, multicentre, double-blind trial. The primary efficacy variable was the proportion of patients healed at week 8. Secondary variables included healing and heartburn resolution at week 4, time to first resolution and sustained resolution of heartburn, and per cent of heartburn-free days and nights. Safety and tolerability were also evaluated.

Results:

Significantly more patients were healed at week 8 with esomeprazole 40 mg (94.1%) and 20 mg (89.9%) vs. omeprazole 20 mg (86.9%), using cumulative life table estimates, ITT analysis (each P < 0.05). Esomeprazole 40 mg was also significantly more effective than omeprazole for healing at week 4 and for all secondary variables evaluating heartburn resolution. The most common adverse events in all treatment groups were headache, abdominal pain and diarrhoea.

Conclusion:

Esomeprazole was more effective than omeprazole in healing and symptom resolution in GERD patients with reflux oesophagitis, and had a tolerability profile comparable to that of omeprazole.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

Significant advances have been made over the past decade in understanding the epidemiology and symptomatology of gastro-oesophageal reflux disease (GERD) with and without oesophagitis. Reflux symptoms are common in the general adult population. Recent US surveys indicate that more than 60 million adult Americans suffer from heartburn at least once a month, and 25 million adults experience heartburn on a daily basis.1 Of patients presenting with GERD symptoms, it is now estimated that 40–60% or more have reflux oesophagitis (RO).2[3]–4 Irrespective of the presence or absence of oesophagitis, GERD patients generally report decreases in productivity, quality of life and overall well-being.5, 6 Many rate their quality of life to be lower than that reported by patients with untreated angina pectoris or heart failure.7

The severity of GERD is directly correlated with the degree and duration of oesophageal exposure to acid refluxate.8[9]–10 Chronic exposure has been associated with serious complications including oesophageal stricture in 4–20% of patients8 and Barrett’s oesophagus in up to 15% of patients with GERD.8[9][10]–11 Healing of RO has been directly correlated with the amount of time intragastric pH is > 4.0.12, 13

While knowledge about GERD is accelerating, advances in pharmacotherapy to treat this disease have not progressed since the first proton pump inhibitor, omeprazole, revolutionized the treatment of GERD over a decade ago.14[15]–16 Since that time, no proton pump inhibitor has surpassed the clinical efficacy of omeprazole in the treatment of GERD.17[18][19][20][21]–22 Early pharmacokinetic and pharmacodynamic trials with the novel proton pump inhibitor esomeprazole, the S-isomer of omeprazole, have yielded some promising findings. Compared with omeprazole, esomeprazole is subject to less first-pass hepatic metabolism and lower plasma clearance. This results in high systemic bioavailability. The area under the plasma concentration–time curve (AUC) for esomeprazole 20 mg has been shown to be 70% higher than that of omeprazole 20 mg, and repeated administration of esomeprazole has resulted in greater inhibition of pentagastrin-stimulated acid secretion as compared with omeprazole (90% vs. 79%).23 In a separate study of patients with GERD symptoms, the AUC has been shown to be 2-fold higher for esomeprazole vs. omeprazole after a 20-mg dose of each compound, and 5-fold higher for esomeprazole 40 mg vs. omeprazole 20 mg (each P < 0.0001). Furthermore, esomeprazole 40 mg and 20 mg maintained intragastric pH > 4 for 16.8 and 12.7 h, respectively, vs. 10.5 h for omeprazole 20 mg (P < 0.001 and P < 0.01). Esomeprazole was also associated with less interpatient variability in both intragastric pH and AUC than was omeprazole.24

These findings prompted further study to evaluate the efficacy (healing and symptom resolution) and tolerability of once-daily doses of esomeprazole 40 mg and 20 mg, compared to omeprazole 20 mg in a large population of patients with RO.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

Study design and patient selection

This double-blind, randomized, multicentre, parallel-group trial was conducted at 140 centres in the United States. All patients provided written informed consent prior to being enrolled in the trial. At baseline screening, patients with symptoms of GERD underwent esophagogastroduodenoscopy (EGD). Mucosal breaks were graded according to the Los Angeles (LA) Classification (Table 1).25 Patients with confirmed RO (LA grades A–D) were eligible for inclusion in the study. Given the multicentre nature of this trial, the LA Classification was chosen because it offers a high degree of interobserver reliability among experienced endoscopists.26 Patients were excluded if they tested positive for Helicobacter pylori at serology screening to eliminate a potentially confounding variable in assessing the efficacy of study medications. Final determination of H. pylori status was made by evaluation of the gastric biopsy samples obtained from the antrum and corpus. Patients found to be H. pylori positive based on the subsequent biopsy results were allowed to remain in the study.

Table 1.  . Los Angeles Classification of Oesophagitis (adapted from reference 25) Thumbnail image of

Patients were not included if they had any bleeding disorder or signs of gastrointestinal (GI) bleeding within 3 days prior to randomization, or had a history of gastric or oesophageal surgery. Patients were also excluded if they had evidence of Zollinger–Ellison syndrome, primary motility disorders, oesophageal stricture, Barrett’s oesophagus (> 3 cm), evidence of upper GI malignancy, severe concomitant disease, or if they were pregnant or lactating. Additionally, patients who had received either proton pump inhibitor therapy within 28 days of the baseline visit or an H2-receptor antagonist on a daily basis during the 2 weeks prior to baseline endoscopy, patients taking nonsteroidal anti-inflammatory drugs or other concomitant medication that might affect the interpretation of the treatment outcome (e.g. diazepam, quinidine, Dilantin, warfarin, anticholinergics, prostaglandin analogs, or sucralfate), and those with a known hypersensitivity to omeprazole or aluminium/magnesium hydroxide (Gelusil; Parke Davis, NJ), were excluded. Other medication considered necessary for the patient’s welfare could be given at the discretion of the investigator.

Eligible patients were randomized to receive once-daily therapy with esomeprazole 40 mg, esomeprazole 20 mg, or omeprazole 20 mg (Figure 1), which is the usual recommended dose of omeprazole for patients with RO and accompanying symptoms. Patients were instructed to take the study medication in the morning. Compliance was assessed through unused capsule count. Patients were permitted to use an aluminium/magnesium hydroxide antacid preparation as a rescue medication throughout the study. To ensure blinding, all three study drugs and bottles had the same appearance. Investigators were provided with individually sealed and blinded randomization envelopes indicating the treatment allocation for each patient.

image

Figure 1. . Trial profile.

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Efficacy assessments

The primary efficacy variable was endoscopically confirmed healing of RO after 8 weeks’ treatment. Following the baseline visit, patients were evaluated 4 and 8 weeks after starting study medication. At both the 4- and 8-week visits an EGD was performed by the investigator. Patients with normal endoscopic appearance (absence of mucosal breaks per protocol using the LA Classification Grading system) during either the week 4 or week 8 visit were considered to be healed. If healing was observed at week 4, the patient was discharged from the study. If RO was still present at this time, the patient received an additional 4 weeks of treatment. Secondary efficacy variables included complete resolution of heartburn as assessed by the investigator at week 4 and 8. Heartburn was graded on a 4-point scale: none, mild (awareness of heartburn but easily tolerated), moderate (discomfort sufficient to interfere with normal activities, including sleep), and severe (incapacitating with inability to perform normal activities, including sleep). Investigators also evaluated the use of antacids. Patients used daily diary cards during the first 4 weeks of the study to record episodes of heartburn experienced during the previous 24 h, as well as the presence of nocturnal heartburn. Patients graded heartburn using the same 4-point grading scale as the investigators. Percentage of heartburn-free days and nights, time to first resolution of heartburn, and time to sustained resolution of heartburn (defined as the first day of the heartburn-free period) were evaluated using diary card data. Resolution was defined as heartburn recorded as ‘none’ and sustained resolution was defined as 7 consecutive days with heartburn recorded as ‘none’.

Adverse event assessment

During each follow-up visit, investigators questioned the patients about the occurrence of adverse effects. All adverse events were recorded, regardless of likely causal association with study medication. The relationship of an adverse event to the study drug was classified by the investigator as probable, possible or unlikely and the intensity as mild, moderate or severe. Sub-analyses were conducted to evaluate the incidence of adverse events in terms of gender, age and race.

Statistical analysis

The primary efficacy variable was analysed on an intention-to-treat basis. The results from patients who were healed at week 4 were carried over to week 8, based on the assumption that the patients who were healed would remain healed if they had continued the same therapy for the full 8 weeks. A log-rank test was used to evaluate between-group differences with respect to the percentage of patients healed at 8 weeks, applying the Hochberg procedure to correct for multiple comparisons (each esomeprazole treatment group compared to omeprazole) and maintain the level of significance at α=0.05. The percentage of patients healed adjusted for baseline RO severity (LA Classification) was evaluated using the Cochran-Mantel-Haenszel (CMH) test. All patients with missing (i.e. no postbaseline endoscopy results) or inappropriate data were considered treatment failures for the CMH analysis.

Severity of heartburn was recorded by both investigator and patient. The analysis of the investigators’ assessments of heartburn was stratified by baseline severity and analysed using the Cochran-Mantel-Haenszel test. The number of days until the first heartburn-free day and the number of days until sustained resolution of heartburn based on patient diary data were analysed using a log-rank test. Between-group differences with respect to the proportion of heartburn-free days (24-h period) and nights were compared using analysis of variance.

With 95% power to detect at least a 10% difference in RO healing rate between omeprazole and esomeprazole, a sample size of 560 patients in each group was required. A two-sided test using arcsine transformation and Bonferroni correction for the comparison of each esomeprazole dose with omeprazole was assumed for sample size calculation.

Incidence rates of adverse events were assessed throughout the 8-week study period, and expressed as the number of patients experiencing at least one adverse event for those who received at least one dose of study drug.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

Patient characteristics

A total of 3354 patients who presented with symptoms of GERD were screened for possible inclusion in the trial, and a total of 1960 patients were randomized to study medication. Patient demographics and baseline characteristics were comparable among the treatment groups (see Table 2). The primary reasons for exclusion from the trial were similar across all treatment groups (Figure 1). Forty-four patients did not complete the study due to an adverse event and 115 for other reasons included being lost to follow-up and withdrawal of consent. Overall patient medication compliance rates during the study were similar across treatment groups, and approached 90%.

Table 2.  . Patient demographics and baseline characteristics Thumbnail image of

Efficacy

Both once-daily doses of esomeprazole, 40 mg and 20 mg, were significantly superior to omeprazole 20 mg once daily after 8 weeks of treatment. Esomeprazole 40 mg provided the greatest life table estimate healing rate, 94.1%, vs. 89.9% for esomeprazole 20 mg and 86.9% for omeprazole 20 mg (P < 0.001 for E40 vs. O20 and P < 0.05 for E20 vs. O20). A significantly higher proportion of patients were healed at week 4 during esomeprazole 40 mg therapy compared with omeprazole 20 mg (Table 3). This greater efficacy for esomeprazole 40 mg vs. omeprazole 20 mg was seen consistently when adjusting for baseline oesophagitis grade and remained statistically significant after 8 weeks’ treatment based on crude rates (Figure 2). At week 4, the difference between the esomeprazole 20 mg vs. omeprazole 20 mg group was not statistically significant (P=0.09). There were no differences in healing at week 8 between the three groups with respect to age or gender.

Table 3.  . Healing rates of reflux oesophagitis in the intention-to-treat population Thumbnail image of
image

Figure 2. . Comparison of RO healing rates at week 8 by baseline severity grade using crude rates (LA Classification). *P < 0.05 for CMH test, esomeprazole 40 mg vs. omeprazole 20 mg.

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One of the criteria for exclusion from the study was a positive serology for H. pylori. On subsequent biopsy analysis 189 patients (9.6%) had histological evidence of H. pylori infection. The study was not powered to detect a statistical difference by H. pylori status, however efficacy in healing was tabulated separately for these patients. The proportion of patients healed at week 4 was 81.5% and 73.2% for esomeprazole 40 mg and 20 mg, respectively, in the H. pylori positive groups vs. 69.9% and 65.7% in the H. pylori negative groups. At week 8, healing was observed in 89.2% and 85.7% of H. pylori positive patients on esomeprazole 40 mg and 20 mg, respectively, vs. 87.3% and 83.6% in the H. pylori negative groups.

Esomeprazole 40 mg produced significantly greater results for all secondary variables that evaluated heartburn resolution (see Table 4), including complete heartburn resolution, time to first resolution of heartburn, time to sustained resolution of heartburn, and percentage of heartburn-free days. Both dosages of esomeprazole, 40 mg and 20 mg, achieved a significantly greater proportion of heartburn-free nights than omeprazole therapy. The cumulative percentage of patients experiencing sustained resolution of heartburn was consistently higher with E40 and E20 vs. O20 over the 4-week period (Figure 3). A cumulative analysis at week 8 was not done because patients could complete the study at week 4 with healed RO, even if symptoms were present.

Table 4.  . Heartburn resolution rates Thumbnail image of
image

Figure 3. . Cumulative percentage of patients experiencing sustained resolution of heartburn in the intention-to-treat population.

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There was a statistically significant correlation between symptom resolution and oesophageal healing in this study. Patients whose heartburn was resolved at week 4 were healed 83.2% of the time with esomeprazole 40 mg and 73.1% of the time with omeprazole 20 mg (P < 0.001 for E40 vs. O20).

Safety and tolerability

Of the 1960 patients randomized to study medication, 1957 received at least one dose of a study drug and were therefore included in the tolerability analysis. Overall, the incidence and profile of adverse events were comparable between treatment groups (see Table 5). No serious drug-related adverse events were reported. The percentage of patients who discontinued therapy due to an adverse event were comparable among the three treatment regimens at 2.0%, 2.6% and 2.0% for esomeprazole 40 mg and 20 mg, and omeprazole 20 mg, respectively. One fatality occurred in the esomeprazole 20 mg group (myocardial infarction), but this was considered not to be drug related. No clinically relevant differences in the number of patients experiencing adverse events were observed when evaluated according to gender, age or race.

Table 5.  . Adverse events occurring in ≥ 3% of patients receiving any study drug during the 8-week study period Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

This is the first head-to-head clinical trial to demonstrate significantly greater healing rates of a proton pump inhibitor vs. omeprazole 20 mg once daily in the treatment of RO and related symptoms. A review of the literature shows that comparative trials with lansoprazole 30 mg once daily,27[28][29][30][31]–32 rabeprazole 20 mg once daily,33[34]–35 or pantoprazole 40 mg32[33][34][35][36][37]–38 demonstrate healing rates comparable to omeprazole 20 mg at 4 and 8 weeks. The present study demonstrates that both doses of esomeprazole, 40 mg and 20 mg, were significantly more effective than omeprazole 20 mg in healing RO at week 8. Esomeprazole 40 mg provided the highest healing rates. Furthermore, more patients were healed in a shorter period of time with esomeprazole 40 mg as evidenced by significantly higher healing rates at week 4. Esomeprazole 40 mg continued to produce a significantly higher proportion of healed oesophageal lesions compared with omeprazole when adjusting for baseline grade of severity. This trial also demonstrated that esomeprazole treatment resulted in faster and more sustained resolution of heartburn compared with omeprazole. Of particular note, a significantly higher percentage of heartburn-free nights were observed in patients treated with esomeprazole vs. omeprazole. Lind et al.24 had demonstrated that intragastric pH is maintained above 4.0 for 6 h longer with esomeprazole 40 mg vs. omeprazole 20 mg and that the difference was most apparent between 12 and 20 h after a morning dose.

The significant correlation between symptom resolution and oesophageal healing with esomeprazole in this study is consistent with data in a meta-analysis by Carlsson et al.,39 which evaluated the relationship between symptoms, endoscopic findings and treatment outcome in 3242 RO patients treated short-term with omeprazole or ranitidine. In that trial, patients whose heartburn was resolved at week 4 were healed 73.3% of the time with omeprazole 20 mg. The investigators concluded that absence of symptoms with omeprazole closely predicted endoscopic healing. Data from the current trial indicates that heartburn was resolved in 73.1% of patients on omeprazole 20 mg and 83.2% of patients on esomeprazole 40 mg.

The correlation between symptom resolution and health-related quality of life (HRQL) was not assessed in the current trial. Published data on this subject are sparse, despite the fact that the negative impact of GERD is well established. A new study by Revicki et al.40 does provide a summary of the findings of three HRQL trials assessing 1406 symptomatic GERD patients. The authors conclude that sustained heartburn resolution, i.e. 7 consecutive heartburn-free days, was consistently associated with statistically significant improvements in patients’ HRQL compared with patients who continued to experience GERD symptoms while on therapy. Reaching the rigorous end-point of complete symptom resolution does appear to offer HRQL benefits to GERD patients.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

The present study demonstrates that esomeprazole is more effective than omeprazole in healing across all grades of oesophagitis and in heartburn resolution, and that esomeprazole had a tolerability profile comparable to that of omeprazole.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References

We gratefully acknowledge the assistance of Paul Rogers in facilitating the conduct of this study, David J. Magner with statistical analyses, Paul Jansson and Eileen Gallagher with manuscript preparation, and the diligent efforts of the study co-ordinators at the investigation sites.

This study was supported by a grant from AstraZeneca LP, Wayne, PA.

The Esomeprazole Study Investigators: D. R. Abrahm, Newport Beach Orange Coast Endoscopy Center; N. Afdhal, Boston Medical Center; M. Ali; K. H. Ashby, Pacific Coast Clinical Coordinators; R. D. Baerg, Tacoma Digestive Disease Center; S. Bank, Long Island Jewish Medical Center; C. F. Barish; I. Bassan; M. N. Baz, Asthma and Allergy Center; J. Behar, Rhode Island Hospital; S. B. Benjamin, Georgetown University Medical Center; R. W. Bennetts, Northwest Gastroenterology Clinic; M. M. Berenson, University of Utah Hospital; T. Bianchi, Community Medical Arts Center; D. Biery; C. A. Birbara, Clinical Pharmacology Study Group; P. C. Bird, Research Associates of Norman, Inc.; V. A. Botoman, Cleveland Clinic Florida; E. M. Bozymski, UNC Memorial Hospitals; J. R. Breiter; J. R. Caldwell; D. Campbell; A. Caos; D. O. Castell; R. Cazen, Davies Medical Center; R. Chiprut, Research Foundation of America, LLC; L. B. Cohen; D. W. Collins, Western States Clinical Research; A. F. Cutler, Sinai Hospital; C. Dasher, Norwood Clinic Research Center; J. Davis, Jackson Foundation/Physicians Plus; D. S. Dickinson, Alabama Gastroenterology; D. W. Dozer, Advanced Clinical Research; M. Draelos, CornerStone Research Care; M. Efrusy, Olympia Fields Osteopathic Hospital; M. Eisner, Florida Medical Clinic; S. Esposito, Endoscopy Site; C. Fausel, The Oregon Clinic, PC-GI Division; M. S. Fedotin; J. Fidelholtz; R. Fisher, Temple University Hospital; S. Fitzgerald, Piedmont Medical Research Associates; R. D. Folan; C. Forsmark, J. Hillis Miller Health Center; F. C. Fowler, University Gastroenterology; F. Frachtman, Center for Clinical Research—Austin; S. Freeman; G. Friedman; S. P. Gaddam; F. A. Gallo, Gastroenterology Association of Suffolk, PC; D. J. Geenen, Wisconsin Center for Advanced Research; G. Gibbons, Remington-Davis, Inc.; M. Goldhamer; J. Goldstein, Brachfeld Medical Associates; J. M. Gordon, University Hospitals of Cleveland; A. Gottesman, Hill Top Research, Inc.; R. C. Gove, The Jersey Foundation Group, Inc.; D. E. Gremillion, Nashville Research Associates; F. Gress, Winthop Hospital GI Department; L. Griffel, Robert Wood Johnson Medical School; P. J. Gulden, Southeastern Clinical Research Consultants; W. V. Harford, Dallas VAMC; A. Harris, New York Hospital Medical Center of Queens; D. Hassman, FPA Medical Group; J. Heaton, Sierra Biomedical; A. M. Heiner, Pharmacology Research Corporation; S. E. Hunt; D. A. Ingis, Burlington County Internal Medicine; M. M. Jamal, UNM Health Sciences Center; D. S. James; J. F. Johanson, Rockford Gastroenterology Association; D. A. Johnson, Digestive and Liver Disease Specialists; R. B. Johnson, Sharp Rees-Stealy Medical Group; J. H. Johnston III, Mississippi Center for Clinical Research, LLC.; J. Jolley; P. J. Kahrilas, Northwestern University; R. Kamyar, Institute of HealthCare Assessment, Inc.; H. Kavin, Lutheran General Hospital; P. King; J. Klingenstein; L. Y. Korman, Metropolitan Gastroenterology Group, PC; G. Koval, St. Vincent Hospital; F. T. Kucer, GrandView Medical Research; M. D. Kurtz, Research Across America; J. A. Ladenheim, Mitchell Pappas Associates; M. Lamet; J. Leavitt; S. Levenson; J. S. Levine, University of Colorado Health Sciences Center; M. S. Levine, Digestive Care Associates; L. J. Lifton; B. Luxon, St. Louis University School of Medicine; D. Maccini; M. Madan; D. P. Magier; H. N. Maimon, Dayton Area Research Association; S. Marcuard, Medical Center Gastroenterology; R. Marks, ClinSites/SORRA Research Center; J. L. Mauldin, ClinSites/SORRA Research Center; A. McCullough, Metrohealth Medical Center; P. R. McNally, Eisenhower Army Medical Center; J. Medoff; P. Meier, VA Medical Center; J. M. Mertesdorf; D. Miller, Cox Pharmacotherapy Research Division; P. J. Milman; P. B. Miner, Oklahoma Foundation for Digestive Disease; D. W. Morris, Healthcare Research Consultants; V. Motaparthy, Gastroenterology/Endoscopy; W. Murchison, Colorado Springs Health Partners; C. C. Nguyen, Mayo Clinic Arizona; D. J. Pambianco, CGA Research; P. Pardoll, Center for Digestive Disease; W. A. Pearce, Rainier Clinical Research Center, Inc.; D. A. Peura, University of Virginia Health Sciences Center; M. G. Prosky; R. E. Pruitt; E. M. M. Quigley, University of Nebraska Medical Center; D. S. Riff, Associated Gastroenterology Medical Group; A. Rodriquez, Digestive Disease Clinic; J. Rogge, Indianapolis Gastroenterology & Hepatology; W. A. Ross; R. Rothstein, University of Pennsylvania Hospital; B. Rubin; H. A. Rubin, Beverly Hills Gastroenterology Institute; D. A. Ruff, South Texas Clinical Trials, PA; S. Safavi; S. C. Schindler, Central Kentucky Research Associates, Inc.; C. M. Schmitt, Southeastern Clinical Research; J. Schneier, Research-JIS; H. I. Schwartz, Miami Research Associates; U. Shah, Philip J. Bean Medical Center; R. Shaker, Medical College of Wisconsin; M. J. Shaw, Park Nicollet-HQ; H. Siegel, Eastside Comprehensive Medical Center; T. Simmons; W. J. Snape; E. J. Spiotta, Sinai Samaritan Medical Center; W. H. Taub, Amherst Commons; G. Taubman, Allenmore Medical Center; M. S. Touger, Hill Top Research, Inc.; J. Turse, Health Advance Institute; N. Vakil, Sinai Samaritan Medical Center; C. M. Wilcox, University of Alabama at Birmingham; P. J. Winkle, Associated Gastroenterology Medical Group; P. Witt, Greeley Medical Clinic; L. D. Wruble, Memphis Gastroenterology Group; T. Zarchy; A. M. Zfass, Medical College of Virginia Hospitals; F. R. Zwas.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. References
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